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https://doi.org/10.1038/s41467-020-19195-w OPEN Decarboxylative thiolation of redox-active to free and further diversification ✉ Tianpeng Cao1, Tianxiao Xu1, Ruting Xu1, Xianli Shu1 & Saihu Liao 1,2

Thiols are important precursors for the synthesis of a variety of pharmaceutically important sulfur-containing compounds. In view of the versatile reactivity of free thiols, here we report the development of a visible light-mediated direct decarboxylative thiolation reaction of

1234567890():,; redox-active esters to free thiols based on the abundant carboxylic feedstock. This transformation is applicable to various carboxylic , including primary, secondary, and tertiary acids as well as natural products and drugs, forging a general and facile access to free thiols with diverse structures. Moreover, the direct access to free thiols affords an advantage of rapid in situ diversification with high efficiency to other important derivatives such as sulfide, disulfide, thiocyanide, thioselenide, etc.

1 Key Laboratory of Molecule Synthesis and Function Discovery (Fujian Province University), College of Chemistry, Fuzhou University, 350108 Fuzhou, China. 2 State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, 350108 Fuzhou, China. ✉ email: [email protected]

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he construction of molecule libraries with structural and A number of C–S bond formation reactions43–49 functional diversity is crucial for the study in the context have been reported, including the related decarboxylative trans- T 1–3 46–49 of chemical biology and drug discovery .Thiolsare formations pioneered by Barton in 1980s , but a direct radical important precursors for the synthesis of a variety of pharma- thiolation to free thiols remains elusive so far. The challenges for ceutically important sulfur-containing compounds, including the proposed radical decarboxylative thiolation to free thiols sulfonamides, sulfonyl fluorides, , sulfides, disulfides, probably lie in the labile nature of free thiols, which can lead to and so on, by virtue of their high reactivity and valence labile dimerization, undesired transfer, and other side reac- nature, and widely employed in organic synthesis, tions43. In fact, free thiols are commonly used as hydrogen atom preparation, materials science, and biomedicine4–17.Infact, transfer (HAT) catalysts or reagents in radical chemistry50–54, besides their well-known roles in protein structure stabiliza- and the HAT from a primary alkyl thiol to alkyl radicals is a fast tions18,19 and many enzymatic processes20,thiolisalsoone process (ca. 107 M−1s−1)52–54. Therefore, in the decarboxylative of the most targeted sites in post-translational protein mod- thiolation process, the desired thiol product (RSH) formed earlier ification (Fig. 1a)21–23. Inspired by the versatile reactivity of may intercept the newly generated alkyl radicals (R∙), thus leading thiols, we conceived that, based on the feedstock of abundant to the undesired (R-H) formation (Fig. 1c). Nevertheless, , a decarboxylative thiolation of acid-derived in radical polymerization, the chain-transfer agents (CTA) 24–39 * redox-active esters (RAEs) (RCO2A ) to free thiols could employed in reversible addition-fragmentation chain-transfer forge a novel access to various thiols and related derivatives polymerization can readily alter the radical addition rate by 8 −1 −1 with considerable structural diversity. In particular, the dec- adjusting the Z group and increase kadd to above 10 M s arboxylative access to free thiols could allow a further diversi- (Fig. 1, C, below)55,56, which inspired us to focus on the sulfur fication to other sulfur-containing compounds40–42 with a donor search in the beginning. Herein, we report our efforts in multiplied diversity by varying the coupling agents (e.g., with the successful identification of thioamides as an effective various electrophiles E+,Fig.1b). sulfur donor, and the invention of visible light-mediated direct

a Thiols in functionality transformation and protein modification

SH SO2NH2 SO3R SO2F

SH R SO2R SOR SCN

SR SSR etc. Rpn13,PDB ID codes:6co4 SH as targeted site in protein modification

b Diversity-oriented decarboxylative thiolation to free thiols (this work)

CO H Activation CO A* Sulfur source S Diversification S 2 2 R H R E R R E+

• Abundant feedstock Decarboxylative thiolation • Various derivatives • Diverse structures • Multiplied diversity

a b E+ Aa Ab A c CO H c 2 Thiolation SH ... S R R R E B a Bb B c ABC... Diversity ABC... Diversity Ca Cb Cc transfer multiplication Diverse ...... Abundant Reactive thiol derivatives Compound library

c Mechanistic consideration

RSH 7 –1 –1 RH kHAT = ~10 M s Competing Well known (undesired) Decarboxylation CO2A* R R SET Sulfur donor? R SH Unknown (desired)

S S kadd R S S R' Inspiration from RAFT: R + R' 6 8 –1 –1 kadd = 10 –10 M s Z k-add Z Chain transfer agent

Fig. 1 Reaction design. a Thiols in functionality transformation and protein modification. b Diversity-oriented decarboxylative thiolation to free thiols. c Mechanistic consideration and the inspiration from reversible addition-fragmentation chain-transfer (RAFT) polymerization.

2 NATURE COMMUNICATIONS | (2020) 11:5340 | https://doi.org/10.1038/s41467-020-19195-w | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-19195-w ARTICLE decarboxylative thiolation of alkyl RAEs to free thiols. Moreover, found beneficial and further increased the yield to 81% (entry 5 further diversification to other thiol derivatives, such as sulfide, vs. entry 6). The N-H group proved to be crucial for this disulfide, thiocyanide, and thioselenide via in situ trapping, is also transformation. Replacement with either one or two methyl demonstrated. groups (2g and 2h),bothresultedinasharpdropinyield (entries 7 and 8). Moreover, sulfur powder was also tested, but no desired thiol product was observed (entry 9). With 2f as the Results sulfur donor, we conducted a further reaction optimization, Reaction optimization. We commenced our study with the including search for sulfur donors suitable for the radical thiolation photocatalyst, solvent, light source, and so on (for details, reaction, by employing dihydrocinnamic acid-derived RAE (1) please see the Supplementary Tables 2 and 3). Other photo- as the model substrate and Eosin Y-Na2/diisopropylethylamine catalysts, such as Ru(bpy)3Cl2·6H2O and Ir(ppy)3, gave lower (DIPEA) as the photoredox catalytic system (Table 1). Initially, yields (entries 10–13), while Eosin Y was found equally efficient thiourea 2a, which is frequently used as a sulfur donor in the (entry 14). Running the reaction in CH CN could slightly nucleophilic substitution reactions of alkyl halides57,58,was 3 fi ′ enhanced the selectivity (entry 15). Without light or photo- examined rst in the reaction, but only the alkane product 3 catalyst, no reaction or a low yield was observed (entries 16 and was observed (entry 1), indicating the radical reactivity is 17). To our delight, the employment of two equivalents of sulfur substantially different from the polar substitution reactions. donor 2f could further suppress the undesired alkane formation Other thioureas like 2b and 2c were also examined, but neither and increase the yield of the desired thiol product to a decent level of them afforded the desired thiol product (entries 2 and 3). We of 88% in the end (entry 18). then turned our attention to other types of sulfur donor (for more details about the reaction development, please see the Supplementary Figs. 1–9andTable1). To our delight, ben- Substrate scope. With the optimized reaction conditions in zothioamide was found being a promising sulfur donor for this hand, we next examined the reaction scope with a variety of decarboxylative thiolation reaction, and the desired thiol 3 primary, secondary, and tertiary acid-derived RAEs (Fig. 2). could be obtained as the predominant product in 77% yield Some free thiols are volatile and thus isolated in their disulfide (entry 4). We then carried out several modifications on the form by in situ trapping with diphenyl disulfide. These results are of benzothioamides (entries 4–6). Electron- also included in Fig. 2. In cases of primary acids (3–18), we could withdrawing group (-CF3, 2e) led to a decreased yield of 35%, see a good tolerance. Br, Cl, , , and while the introduction of an electron-donating group (2f)was also a triple C–C bond are all compatible in the reaction, and the

Table 1 Reaction optimizations for decarboxylative thiolation to free thiolsa.

O Sulfur donor (1.0 eq) SH O Ph 3 photocatalyst, DIPEA (1.1 eq) N Ph O + DCM, Ar, r.t., 24 h H O Ph 3' 1 6 W Blue LEDs Selected examples of sulfur donor: H S S S N S NH2 HN NH H2N NH2 N H 2a 2b 2c 2d

S S S S

NH2 NH2 N N H F3C MeO MeO 2e 2f 2g 2h

Entry Sulfur donor Yield (3/3′)b Entry Catalyst Yield (3/3′)b

1 2a 0/81 10 [Ru(bpy)3]Cl2·6H2O 71/28 2 2b 0/76 11 Ir(ppy)3 37/32 3 2c 0/79 12 Rhodamine B 76/28 4 2d 77/26 13 Fluorescein 71/36 5 2e 35/28 14 Eosin Y 81/23 d 6 2f 81/23 15 Eosin Y-Na2 83/18 d,e 7 2g 2/72 16 Eosin Y-Na2 0/0 d,f 8 2h 3/97 17 w/o Eosin Y-Na2 38/10 c d,g 9 Sulfur powder 0/0 18 Eosin Y-Na2 88/6 aReaction conditions: 0.05 mmol scale, catalyst (2.5 mol%). Left entries: with Eosin Y-Na2 as the photocatalyst. Right entries: with 2f as the sulfur donor. bDetermined by GC-MS analysis with anisole as an internal standard. cSulfur powder (5.0 equiv.). d Reaction was performed in CH3CN instead of DCM. eIn dark. fWithout photocatalyst. gWith 2.0 equiv. of 2f.

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O 2f (2.0 eq) O Eosin Y-Na2 (2.5 mol%) R SH PhSSPh (2.0 eq) R S Ph R N R' S O DIPEA (1.1 eq), MeCN R' R'' In dark, Ar, r.t., 6 h R' O R'' R'' 6 W Blue LEDs, Ar, r.t., 24 h in situ trapping From 1°, 2° and 3° acids Free thiols

Primary acids Secondary acids

SH SH SH SH SH

SH N N O Br Boc Ac

3, 70% 4, 52% 5, 59% 19, 40% 20, 35% 21, 34%

SH O S Ph S S SH Ph Ph SH S S S Cl

6, 55% 7, 75% 8, 35% 22, 24% 23, 60% 24, 65%

S S Ph CO Me S Ph Ph 2 S S S F SH SH F

9, 81% 10, 32% 25, 53% 26, 35% 27, 73%

Ph S Ph S Ph S S Ph S S S S S Ph S Ph S Ph Ph S O S

11, 72% 12, 65% 13, 41% 28, 64% 29, 50% 30, 54%

Tertiary acids

S Ph S Ph MeO2C S Ph O SH S S S SH SH N 14, 40% 15, 80% 16, 72% O Boc

31, 56% 32, 16% 33, 52%

CO2Me Br S SH Cl S Ph S Ph S Ph S S S S Ph

17, 45% 18, 70% 34, 60% 35, 25%a 36, 39%a

Natural products and drugs

Boc Boc NH NH

O SH O SH tBu tBu SH SH SH O O

37, 74% 38, 72% 39, 62% 40, 37% 41, 46% from from stearic acid from oleic acid from aspartic acid from glutamic acid

SH tBu HO MeO H O Ph SH O O O N SH SH SH N H N O Ph H H HN O Cl O Boc 42, 46% 43, 10%a 44, 24% 45, 49% 46, 32% from dipeptide Glu-Pro from Gemfibrozil from Oxaprozin from Indometacin from nutriacholic acid

Fig. 2 Substrate scope. Reactions were performed on a 0.2 mmol scale, and trapping reactions were conducted with 2.0 equiv. of PhSSPh in dark for 6 h. a In CF3CH2OH. desired free thiols (4–10)ordisulfides (11–18)couldbeisolated applied to cyclic carboxylic acids (19–30), and different ring sizes in moderate to good yields. Through this decarboxylative thio- (22–26), including cyclopropane (22), cyclobutane (23), benzo- lation, simple propionic acid can also be converted to the cor- cyclopentane (21), and cycloheptane (26), all can be converted to responding disulfide in 40% yield (14). The reaction can be well the desired product in reasonable yields. Heterocyclic free thiols

4 NATURE COMMUNICATIONS | (2020) 11:5340 | https://doi.org/10.1038/s41467-020-19195-w | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-19195-w ARTICLE or disulfides, such as 19, 20,and30, are also accessible from the and physiochemical properties61–66. To further explore the corresponding carboxylic acids. Pleasingly, tertiary thiols or scope of this transformation, more diaryl disulfide-trapping disulfide (31–36) can be prepared as well with this method. In agents were examined with dihydrocinnamic acid-derived particular, this visible light-mediated radical decarboxylative ester 1 as a model substrate. As shown in Fig. 3a, the reac- thiolation reaction could afford a facile access to tertiary tions worked well with various diaryl disulfides processing bridgehead thiols (such as bicyclic thiol 31, 1-adamantanethiol different electronic nature, affording the desired unsymmetric alkyl 33 and 34) under mild reaction conditions, which are often aryl disulfides 47–51 readily in good yields. Importantly, the difficult to prepare via traditional nucleophilic substitution conversion of carboxylic acids to disulfides via this dicarboxylic reactions due to the steric shielding of the bridgehead position thiolation/in situ trapping protocol provides a facile approach to that prevents the backside attack of the nucleophiles59.The synthesize this type of molecules with high structural diversity. reported synthesis of 33 from 1-adamantyl bromide or Thiols are key precursors to many pharmaceutically important was performed under very harsh conditions (reflux in AcOH/ compounds4–17,40–45. The direct decarboxylative thiolation to conc. aq. HBr), and under the same conditions, only a trace free thiols allows for the establishment of a rapid, in situ diversi- amount of product was obtained in the synthesis of bicyclo[2.2.2] fication to various thiol derivatives without isolating the free thiols, octane-1-thiol59,60. Moreover, the decarboxylative thiolation which are often smelly and unstable. As shown in Fig. 3b, the reaction can be well extended to natural occurring acids, such as 2-phenylethane-1-thiol can readily undergo alkylation in situ oleic acid (39), aspartic acid (40), glutamic acid (41), dipeptide with various electrophiles or Michael acceptors, to provide the Glu-Pro (42), and nutriacholic acid (46). It is worth mentioning corresponding sulfide products (52–57). Moreover, trapping with that the conversion of aspartic acid to the thiol product 40 is 4-methylbenzenesulfonyl cyanide enable the conversion of car- resembling a transformation of aspartic acid to cysteine via a boxylic acid to thiocyanide 58. An access to thioselenide from residue manipulation. To our delight, this decarboxylative thio- the corresponding carboxylic acid via an in situ reaction with lation can be adopted for the late-stage modification of drugs, was also demonstrated with the synthesis of such as gemfibrozil (43), oxaprozin (44), and indometacin (45). thioselenide 59. In cases of 35, 36,and43, we could observe less alkane formation A possible reaction mechanism is proposed as outlined in when the reactions were performed in CF3CH2OH instead of Fig. 4. Under the irradiation of light, the photocatalyst Eosin Y CH3CN, and thus led to a better yield. As outlined in Fig. 2, (PC) is excited and subsequently reductively quenched by DIPEA under this reaction condition, primary, secondary, and tertiary or 2f, affording PC•− and 2f′ in the presence of base. The radicals can all be readily generated from the corre- fluorescence quenching experiments also clearly showed that both sponding alkyl NHPI esters and subsequently trapped by the DIPEA and sulfur donor 2f can quench the fluorescence of the sulfur donor and converted to the desired thiol or disulfide photocatalyst (Supplementary Figs. 7–9). A single electron products. transfer (SET) from PC•− to the carboxylic acid-derived RAE afford the corresponding radical anion Int-A and concurrently regenerate the photocatalyst (Path A). As product also observed Product diversification.Disulfides are important motifs in life and in the absence of PC and 2f showed substantial absorption in the biological active molecules, due to their unique pharmacological blue light region (Supplementary Fig. 5), Path B might also

a Extension to unsymmetric synthesis

O Standard ArSSAr conditions SH S Ar Ph OA* Ph Ph S In situ trapping 1

CF3 Me Cl OMe S S S S S Ph S Ph S Ph S Ph S Ph S NO2 NO2 47 (65%) 48 (58%) 49 (56%) 50 (54%) 51 (50%)

b In situ diversification to , , thioselenide

S Ph S S Ph Ph Trapping agents: Ph CH3 Ph CO Et 52 (41%) 53 (40%) 2 54 (63%) a)CH3I b) PhCH2Br a) b) c) S CN Ph d) Br O As above 55 (68%) SH c) d) ClCH CN Ph Ph CO2Et 2 Ph OH e) S n f) Ph CO2 Bu O Dihydrocinnamic acid Et h) g) 56 (80%) N n e) CO2 Bu f) O O S S Ph S Ph Ph Se Ph CN N Et g)TsCN h) PhSeSePh 57 (70%) 59 (50%) 58 (65%) O

Fig. 3 Reaction extension and product diversification. a Extension to disulfide synthesis. b In situ diversification.

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R SH

*PC PC = Eosin Y-Na2 ArCN Ar = 4-MeO-C6H4

Elimination DIPEA NH or 2f' R PC S Ar S

Ar NH Int-C

O O SET DIPEA or R 2f / base SET O N

Path A RAE 2f' Path I R O S PC

Path II Ar NH2 Int-B 1/2 2f'-2f' 2f (dimer) O O 2f R O N Path B SET R Int-A O O Competing N + CO RH HAT 2 2f (undesired) O RS RSH

Fig. 4 Reaction pathways. A mechanistic proposal for the decarboxylative thiolation of redox-active esters (RAEs) to free thiols. SET single electron transfer, HAT hydrogen atom transfer. involve to some extent. Int-A then undergoes fragmentation to thioselenide, with diverse structures, which may be utilized for give the alkyl radical R∙ via the N–O bond cleavage followed by the molecule library construction and benefit the related study in the extrusion of CO2. The alkyl radical can be trapped with chemical biology and discovery of novel, biologically interesting TEMPO (Supplementary Fig. 3). The addition of R∙ to the sulfur small molecules. donor 2f generate the radical intermediate Int-B67, which can be oxidized to Int-C by a SET to excited photocatalyst as shown as Path I. The higher yields with aryl thioamides than alkyl Methods ones may be ascribed to the stabilization of the aryl group to General procedure for decarboxylative thiolation. To an oven-dried 10-ml radical Int-B. The beneficial effect of the electron-donating group Schlenk tube equipped with a magnetic stir bar and a Teflon-coated septum (2d–f, entries 4–5, Table 1) might result from a favored one screwcap was added the NHPI redox-active ester (0.2 mmol, 1.0 equiv.), 4- methoxythiobenzamide (2f, 0.4 mmol, 2.0 equiv.), Eosin Y-Na2 (2.5 mol%). The electron oxidation of Int-B to Int-C. Alternatively, a radical tube was evacuated and backfilled with argon for three cycles. The DIPEA (0.22 ∙ ′ coupling of R and 2f could also afford the intermediate Int-C mmol, 1.1 equiv.) and dry CH3CN (2.0 ml) was added via a gastight syringe under (Path II). As a competing process, the HAT from thiol (R-SH) argon atmosphere. Make sure the screwcap was closed, and the solvent was frozen to R∙ will lead to the formation of the alkane side product by liquid nitrogen. Then, the screwcap was opened and the tube was evacuated for 51,52 ∙ about 3 min. The screwcap was closed and let the solvent melts in a tepid water (R-H) , which can be suppressed by a rapid trapping of R bath. Repeat above freeze-pump-thaw procedures for 3–5 times until you no longer with active thiolating agents via Path I or II. In the end, the see the evolution of gas as the solution thaws. The tube was filled with argon and desired thiol is produced after the elimination of one molecule of sealed, irradiated with 6 W blue light-emitting diode (LED) reactor and stirred at ArCN68,69, which could be a relatively slow step, and a slow ambient temperature for 24 h. Full experimental details (Supplementary Figs. 1–9 and Supplementary Tables 1–3) and characterization of new compounds (Sup- release of free thiols can decrease the formation of the undesired plementary Figs. 10–68) can be found in the Supplementary Methods section. alkane product. The byproduct formation was confirmed by gas chromatography-mass spectrometry (GC-MS) analysis, and it can also be isolated by column chromatography. Therefore, General procedure for the synthesis of disulfides. To an oven-dried 10-ml the use of N-unsubstituted thioamides is crucial for this Schlenk tube equipped with a magnetic stir bar and a Teflon-coated septum transformation. In contrast, N-substituted thioamide 2g and 2h screwcap was added the NHPI redox-active ester (0.2 mmol, 1.0 equiv.), 4- methoxythiobenzamide (2f, 0.4 mmol, 2.0 equiv.), and Eosin Y-Na2 (2.5 mol%). are unable to form the corresponding N-H imine intermediate fi Int-C. The tube was evacuated and back lled with argon for three cycles. The DIPEA (0.22 mmol, 1.1 equiv.) and dry CH3CN (2.0 ml) was added via a gastight syringe under argon atmosphere. Make sure the screwcap was closed, and the solvent was frozen by liquid nitrogen. Then, the screwcap was opened and the tube was Discussion evacuated for ~3 min. The screwcap was then closed and the solvents were let to melt in a tepid water bath. Repeat above freeze-pump-thaw procedures for 3–5 In conclusion, a visible light-mediated direct decarboxylative times until you no longer see the evolution of gas as the solution thaws. The tube thiolation of carboxylic acid-derived RAEs to free thiols has been was filled with argon and sealed, irradiated with 6 W blue LED reactor and stirred developed. Aryl thioamides have been identified as an effective at ambient temperature for 24 h. Then, the K2CO3 (0.4 mmol, 2.0 equiv.) and diaryl sulfur donor and crucial to this thiolation reaction. The trans- disulfide (0.4 mmol, 2.0 equiv.) was added under argon atmosphere. The tube stirred at ambient temperature for 6 h in the dark. Upon completion, the reaction formation of abundant carboxylic acid feedstock to the corre- fi fl fi mixture was carefully concentrated and the residue was further puri ed by ash sponding free thiols and their further in situ diversi cation allows chromatography to give the desired disulfide products. Full experimental details for a rapid and general access to various pharmaceutically and characterization of new compounds can be found in the Supplementary important compounds, such as sulfide, disulfide, thiocyanide, and Methods section.

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56. Moad, G., Rizzardo, E. & Thang, S. H. Radical addition–fragmentation Author contributions chemistry in. Polym. Synth. Polym. 49, 1079–1131 (2008). T.C. and T.X. contributed equally to this work. T.C. developed the reactions, and con- 57. Cossar, B. C., Fournier, J. O., Fields, D. L. & Reynolds, D. D. Preparation of tributed to the reaction scope investigation, mechanistic study, and product derivatiza- thiols. J. Org. Chem. 27,93–95 (1962). tion. T.X. carried out most substrate synthesis, and contributed to the study of reaction 58. Wardell, J. L. In The Chemistry of the Thiol Group (ed. Patai, S.), Part 1, scope, product diversification, and reaction mechanism. R.X. and X.S. participated in the 179–211 (Wiley, New York, 1974). synthesis of substrates. S.L. conceived this concept and prepared this manuscript with 59. Tkachenko, B. A. et al. Functionalized nanodiamonds part 3: thiolation of feedback from T.C. and T.X. tertiary/bridgehead . Org. Lett. 8, 1767–1770 (2006). β 60. Moya-López, J. F. et al. Studies on the diastereoselective oxidation of 1-thio- - Competing interests d-glucopyranosides: synthesis of the usually less favoured RS as a single diastereoisomer. Org. Biomol. Chem. 13, 1904–1914 (2015). The authors declare no competing interests. 61. Musiejuka, M. & Witt, D. Recent developments in the synthesis of unsymmetrical disulfanes (disulfides). A review. Org. Prep. Proc. Int. 47, Additional information 95–131 (2015). Supplementary information is available for this paper at https://doi.org/10.1038/s41467- 62. Xiao, X., Feng, M. & Jiang, X. New design of a disulfurating reagent: facile and 020-19195-w. straightforward pathway to unsymmetrical disulfanes by copper‐catalyzed oxidative cross‐coupling. Angew. Chem. Int. Ed. 55, 14121–14125 (2016). Correspondence and requests for materials should be addressed to S.L. 63. Xiao, X., Xue, J. & Jiang, X. Polysulfurating reagent design for unsymmetrical polysulfide construction. Nat. Commun. 9, 2191 (2018). Peer review information Nature Communications thanks Hua Wang and the other, 64. Wang, W., Lin, Y., Ma, Y., Tung, C.-H. & Xu, Z. Cu-catalyzed electrophilic anonymous, reviewer(s) for their contribution to the peer review of this work. Peer disulfur transfer: synthesis of unsymmetrical disulfides. Org. Lett. 20, reviewer reports are available. 3829–3832 (2018). 65. Huang, P., Wang, P., Tang, S., Fu, Z. & Lei, A. Electro‐oxidative S−H/S−H Reprints and permission information is available at http://www.nature.com/reprints cross‐coupling with hydrogen evolution: facile access to unsymmetrical disulfides. Angew. Chem. Int. Ed. 57, 8115–8119 (2018). Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in 66. Chauvin, J.-P. R., Griesser, M. & Pratt, D. A. The antioxidant activity of published maps and institutional affiliations. polysulfides: it’s radical! Chem. Sci. 10, 4999–5010 (2019). 67. Smith, R. A., Fu, G., McAteer, O., Xu, M. & Gutekunst, W. R. Radical approach to containing polymers. J. Am. Chem. Soc. 141, 1446–1451 Open Access This article is licensed under a Creative Commons (2019). Attribution 4.0 International License, which permits use, sharing, 68. Khodade, V. S. & Toscano, J. P. Development of S-substituted thioisothioureas as efficient hydropersulfide precursors. J. Am. Chem. Soc. 140, 17333–17337 adaptation, distribution and reproduction in any medium or format, as long as you give (2018). appropriate credit to the original author(s) and the source, provide a link to the Creative 69. Rad, M. N. S. & Maghsoudi, S. Two-step three-component process for one-pot Commons license, and indicate if changes were made. The images or other third party ’ synthesis of 8-alkylmercaptocaffeine derivatives. RSC Adv. 6, 70335–70342 material in this article are included in the article s Creative Commons license, unless (2016). indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ Acknowledgements licenses/by/4.0/. We gratefully acknowledge National Natural Science Foundation of China (No. 21602028), the Recruitment Program of Global Experts, and Fuzhou University for the financial support. © The Author(s) 2020

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